Studies continue to determine the cellular and molecular mechanisms by which naturally occurring and synthetic estrogenic compounds interact with various target tissues such as the developing genital tract and skeletal system to cause permanent alterations in differentiation, including dysmorphology and neoplasia. Diethylstilbestrol (DES) is used as a model estrogenic compound. In vivo studies in which DES exposure occurred during development of the murine genital tract (prenatally and/or neonatally) have shown benign and malignant lesions in both male and female animals in structures derived from both the Mullerian ducts and the mesonephric ducts. The molecular genetic features of the DES- induced tumors are being studied and compared to those reported in human malignancies. Descendants of the tumor-bearing mice are being followed for reproductive assessment and potential increased susceptibility to tumors. The ontogeny of lactoferrin (LF) and the estrogen receptor (ER) in the developing reproductive tract are being mapped to determine early estrogenic responses and the role of ER in these responses. Transgenic ER mice have been treated developmentally with DES to determine if the ER is playing a role in the induction and/or progression of uterine neoplasia. Dysmorphology in the genital tract of mice exposed developmentally to DES includes the persistent gene expression of uterine lactoferrin, TGF-alpha. and EGF which may be preneoplastic markers. Studies on phospholipid turnover have shown further insights into signal transduction mechanisms associated with estrogens. Since EGF stimulates uterine cell division in the developing and mature reproductive tract, growth factors may play a role in growth and differentiation of these tissues. Furthermore, it was shown that estrogen regulates the expression of both EGF and TGF-alpha. EGF reproduced the effect of estrogen on induction of DNA synthesis, lactoferrin mRNA levels, and phosphoinositide metabolism. The estrogen-like effects of EGF in the uterus of the mature mouse and uterine-derived cells in culture were dependent on the classical estrogen receptor. Together, these studies support a complex developmental progression in hormone responsiveness in the female and male genital tract with important clues for the development of neoplasia.